Mechanisms of strain diversity of disease-associated in-register parallel β-sheet amyloids and implications about prion strains.

Abstract

The mechanism of strain diversity of prions still remains unsolved, because the investigation of inheritance and diversification of the protein-based pathogenic information demands identification of the detailed structures of abnormal isoform of prion protein (PrPSc), while it is difficult to purify for analysis without affecting the infectious nature. On the other hand, the similar prion-like properties are recognized also in other disease-associated in-register parallel {beta}-sheet amyloids including Tau and -synuclein (Syn) amyloids. Investigations into structures of those amyloids by solid-state nuclear magnetic resonance spectroscopy and cryo-electron microscopy recently made remarkable advances, because of their relatively small sizes and lack of post-translational modifications. We review the advances on those pathogenic amyloids, particularly Tau and Syn, and discuss their implications about strain diversity mechanisms of prion/PrPSc from the viewpoint that PrPSc is an in-register parallel {beta}-sheet amyloid. We also present our recent data of molecular dynamics simulations of Syn amyloid, which suggest significance of compatibility between {beta}-sheet propensities of the substrate and local structures of the template for stability of the amyloid structures. Detailed structures of the Syn and Tau amyloids are good surrogate models of pathogenic amyloids including PrPSc to elucidate not only the strain diversity but also their pathogenic mechanisms.